The purpose of these studies is to evaluate the therapeutic potential of the angiogenesis inhibitors thrombospondin-1, angiostatin, and endostatin, for gene therapy of rheumatoid arthritis. Using lentiviral and helper-dependent adenoviral vectors as gene delivery systems for these angiogenesis inhibitors, we propose to develop an intra-articular treatment for rheumatoid arthritis. A considerable body of experimental and clinical data has documented that the pathogenetic process in rheumatoid arthritis involves the induction of a neovascular response. The process of new blood vessel formation, or angiogenesis, involves the interaction of substances that either stimulate or inhibit endothelial cell proliferation and migration. During pathologic processes such as rheumatoid arthritis, increased expression of angiogenic stimulators or decreased production of inhibitors alters the balance of positive and negative inputs of endothelial cell proliferation in favor of active neovascularization. We hypothesize that by increasing the concentration of these angiogenesis inhibitors in the synovial tissues during chronic inflammation, we may prevent the induction of new blood vessels and retard disease progression. The proposed experiments will allow us to: 1) optimize delivery and expression of transgenes encoding the angiogenesis inhibitors thrombospondin-1, endostatin and angiostatin, following intra- articular administration of lentiviral and helper-dependent adenoviral vectors, 2) to determine the extent of systemic absorption and investigate the systemic effects of intra- articularly delivered anti-angiogenic lentiviral and adenoviral vectors, 3) to determine the in vivo chemopreventive effects of increased local expression of angiogenesis inhibitors on the establishment of arthritic disease, and 4) to determine the ability of lentiviral-and adenoviral-mediated delivery and local overexpression of anti-angiogenic genes to inhibit disease progression and angiogenesis in established arthritis. The development of an effective anti-angiogenic therapy for rheumatoid arthritis utilizing a relatively non-invasive intra- articular gene delivery strategy could have significant impact on patient quality of life, and potentially improve long-term outcome. In addition, by taking advantage of the ease of access by the intra-articular route, we anticipate that it will be possible to establish high local concentrations of potent angiogenic inhibitors while minimizing potentially adverse effects associated with systemic administration.